An efficient enzymatic approach to (S)-1-aryl-allylamines

Article abstract of DOI:10.1016/j.tetasy.2011.06.004

A range of 1-aryl-allylamines were prepared in moderate to excellent enantioselectivity (ee 63.5%→99.9%) using lipase B from a Candida antarctica catalyzed resolution of racemic amines. This is the first time that CaLB has been used for the resolution of 1-aryl-allylamines. Racemic amines were prepared starting from aromatic aldehydes with a [3,3]-sigmatropic rearrangement of the acyclic imidates as the key step followed by trichloroacetamidate hydrolysis. Aldehydes were converted into acrylic esters using Knoevenagel reaction. After reduction, the corresponding alcohols were used for the preparation of trichloroacetimidates, which were then used in an Overman rearrangement.

Full text of DOI:10.1016/j.tetasy.2011.06.004

Tetrahedron: Asymmetry 22 (2011) 936–941
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An efficient enzymatic approach to (S)-1-aryl-allylamines
a
b
a
a,
⇑
ˇ
´
´
Anamarija Knezevic , Goran Landek , Irena Dokli , Vladimir Vinkovic
a
-
´
Department of Organic Chemistry and Biochemistry, Ruder Boškovic Institute, PO Box 180, 10002 Zagreb, Croatia
Galapagos Istrazivacki Centar d.o.o., Prilaz Baruna Filipovi´ca 29, 10000 Zagreb, Croatia
b
ˇ
ˇ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 March 2011
Accepted 2 June 2011
A
range of 1-aryl-allylamines were prepared in moderate to excellent enantioselectivity (ee
63.5%?99.9%) using lipase B from a Candida antarctica catalyzed resolution of racemic amines. This is
the first time that CaLB has been used for the resolution of 1-aryl-allylamines. Racemic amines were pre-
pared starting from aromatic aldehydes with a [3,3]-sigmatropic rearrangement of the acyclic imidates as
the key step followed by trichloroacetamidate hydrolysis. Aldehydes were converted into acrylic esters
using Knoevenagel reaction. After reduction, the corresponding alcohols were used for the preparation
of trichloroacetimidates, which were then used in an Overman rearrangement.
Ó 2011 Elsevier Ltd. All rights reserved.
O
Ar
1. Introduction
O2N
Ar
NH2
H
O
N
H
Enantiomerically pure primary chiral amines with a stereogenic
Ar
center at the
a-position are very important building blocks in or-
ganic chemistry.1 An additional allylic functionality at the stereo-
genic carbon center increases their synthetic potential. These
types of compounds have been used as starting materials for the
synthesis of different amino acids, alkaloids, and nitrogen contain-
ing molecules, which possess a wide range of biological activities.2
One method for obtaining enantiomerically pure chiral amines is
the resolution of racemic amines by enzymes, in particular the
Candida antarctica lipase B (CaLB) catalyzed enantioselective acyl-
ation. This enzyme has proven to be a very effective catalyst for
the resolution of primary amines with a stereogenic center at the
NO2
Scheme 1. Retrosynthetic pathway toward chiral selectors.
the Overman rearrangement of allyl trichloroacetimidates as the
method for our synthesis.7
In the first step of the synthesis, acrylic esters 2a–f were pre-
pared from the corresponding aromatic aldehydes, using
a
DMAP/piperidine catalyzed Knoevenagel reaction with ethyl
hydrogen malonate generated in situ from ethyl potassium malon-
ate using acetic acid.8 The reaction mixture was heated in DMF, at
60 °C for 5–8 days to afford acrylic esters with 1-naphthalenyl 2a,
4-methylphenyl 2b, 3,5-dimethylphenyl 2c, 2-methylphenyl 2d,
2,4,6-trimethyphenyl 2e, and 4-methylnaphthalen-1-yl 2f substit-
uents (Table 1). All of the esters were obtained with an (E)-config-
uration of the double bond which is essential for the later Overman
rearrangement. Due to the two methyl groups that sterically
hinder the carbonyl carbon, ester 2e was obtained in a lower yield
a
-position due to the high stereoselectivity and simplicity of the
resolution process.3
As part of our ongoing research on brush-type chiral stationary
phases,4 we envisaged the synthesis of a series of chiral selectors
containing a terminal double bond, which is required for binding
to a silica surface.5 Chiral 1-aryl-allylamines have been recognised
as key intermediates in this synthetic pathway (Scheme 1).
Herein we report the synthesis of racemic 1-aryl-allylamines
and their resolution using lipase B from C. antarctica. This is the
first time that CaLB has been used for the resolution of allyl amines.
Table 1
Synthesis of aromatic allyl alcohols 3a–f from the corresponding aldehydes
2. Results and discussion
Aldehyde
Ar
2, Yield (%)
3, Yield (%)
Among the different methods for the preparation of the allyl
amines,6 and due to the availability of starting materials, we chose
1a
1b
1c
1d
1e
1f
1-Naphthalenyl
4-Methylphenyl
3,5-Dimethylphenyl
2-Methylphenyl
2,4,6-Trimethylphenyl
4-Methylnaphthalen-1-yl
95
99
98
97
53
95
99
99
98
96
99
99
⇑
Corresponding author. Tel.: +385 14680108; fax: +385 14571300.
E-mail address: Vladimir.Vinkovic@irb.hr (V. Vinkovic´).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.004

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A. Knezevic et al. / Tetrahedron: Asymmetry 22 (2011) 936–941
and with a considerable amount of the reactant remaining intact,
even after the reaction had been performed for 20 days.
Acrylic esters 2a–f were then reduced in excellent yields to give
allyl alcohols 3a–f using DIBAL-H (Fig. 1 and Table 1). The reactions
were performed in dichloromethane for 2 h. The cinammyl alcohol
3g was not synthesized due to its commercial availability.
conditions were optimized on phenylallylamine 6g and later applied
to other amines with some modifications. Amine resolutions were
performed using C. antarctica lipase B in MTBE or hexane at 30 °C.
Ethyl methoxyacetate and iso-propyl acetate were used as acyl do-
nors (Table 3). In the case of amines 6a, 6b, 6f, and 6g, excellent
ee’s were obtained. The absolute configuration of the amines was as-
sumed to be (S), which is in accordance with Kazlauskas rule and the
previously reported results in which CaLB always preferentially
transformed the (R)-enantiomer of a racemic amine, leaving the
(S)-enantiomer unchanged.10 This assumption was confirmed by
comparing the specific rotation measured for (S)-phenylallylamine
AcOH, DMAP
piperidine
CO2Et
CO2K
O
CO2Et
Ar
+
Ar
H
DMF, 60 °C
5-8 d
(S)-6g prepared by the resolution of the diastereomeric salts.11
A
2a-f
1a-f
lower ee was observed in the case of amines 6c. It was also noticed
that the presence of a methyl group at the ortho-position resulted
in a lower enantioselectivity for amine 6d, and in almost no enanti-
oselectivity for amine 6e which has two ortho-methyl groups.
1M DIBAL-H in toluene
Ar
OH
CH2Cl2, -20 °C
to 0 °C, 2h
3a-f
3. Conclusion
Figure 1. Synthesis of aromatic allyl alcohols 3a–f from the corresponding
aldehydes.
Racemic 1-aryl-allylamines with 1-naphthalenyl rac-6a, 4-
methylphenyl rac-6b, 3,5-dimethylphenyl rac-6c, 2-methylphenyl
rac-6d, 2,4,6-trimethyphenyl rac-6e, 4-methylnaphthalen-1-yl
rac-6f, and phenyl rac-6g substituents were prepared starting from
corresponding aldehydes in an excellent overall yield (five steps,
41–78%) with an Overman rearrangement as the key step. The
enzymatic resolution of the racemic amines rac-6a–f was success-
fully performed using lipase B from C. antarctica to give amines 6a–
f in moderate to excellent enantiomeric excess (63.5% to >99.9%).
This is the first time CaLB has been used for the resolution of 1-
aryl-allylamines. The double functionality classifies the enantioen-
riched allyl amines as interesting chiral building blocks with a
wide range of further synthetic applications.
Allyl alcohols 3a–g were converted into trichloroacetimidates
4a–g in a DBU catalyzed reaction with trichloroacetonitrile (Fig. 2).
Reactions were performed in dichloromethane at 0 °C and were
complete after 15 min. Products 4a–g were obtained after filtration
over a short column of neutral aluminium oxide in 89–96% yield. The
Overman rearrangement of allyl trichloroacetimidates 4a–g gave
2,2,2-trichloro-N-(1-arylallyl)acetamides 5a–g in 68–96% yield.
The rearrangement was conducted thermally by heating the
reaction mixture at reflux in xylene. Although some catalytic asym-
metric Overman rearrangements of aliphatic allylic trichloroacetim-
idates resulted in high yields and excellent ee’s, the corresponding
reaction of the aromatic compounds has not yet been successfully
performed.9 Racemic amines rac-6a–g were obtained in good yield
after amide hydrolysis using 5 M NaOH (Table 2).
4. Experimental
4.1. General
NH
Cl3CCN, DBU
Ar
OH
Ar
O
CCl3
CH2Cl2, 0 °C,
30 min
All reactions were conducted under an argon atmosphere unless
otherwise noted. THF was distilled from sodium/benzophenone ke-
tyl and CH2Cl2 was distilled from CaH2. All other reagents and sol-
vents were purchased from commercial sources and used without
purification. Lipase acrylic resin from C. antarctica (Novozym 435,
10000 U/g) was obtained from Sigma Aldrich. TLC was performed
on aluminium backed silica plates (60 F254, Merck) or aluminium
backed aluminium oxide plates (neutral 60 F254, Merck). UV light
(254 nm) or phosphomolibdic acid reagent were used for visualiz-
ing. Column chromatography was performed on silica gel (Silica
Gel 60, 70–230 mesh, Fluka) or aluminium oxide (Merck Alumini-
umoxide 90 active, neutral, activity I). 1H and 13C NMR were re-
corded on a Bruker AV 300 spectrometer. Chemical shifts (dH and
dC) are quoted in parts per million (ppm), referenced to TMS. Optical
rotations were measured using Optical Activity AA-10 automatic
polarimeter. HPLC measurements were done using a Shimadzu LC-
20 system or Knauer system equipped with Pump 64, 4-Port Knauer
Degasser, UV detector Knauer Variable Wavelength Monitor, Inter-
face Knauer, and CD detector Jasco CD-2095. Chiral LC analyses of
the final amines were performed on a Daicel Chiralcel OD-H column,
250 mm ꢀ 4.6 mm. Melting points were determined on Electrother-
mal 9100 apparatus in open capillaries and are not corrected. IR
spectra were recorded on a Bruker ABB Bowen instrument.
4a-g
3a-g
Ar
Ar
O
K2CO3
5M NaOH
NH2
N
H
CCl3
xylene reflux,
20 h
EtOH, rt, 20 h
6a-g
rac-
5a-g
Figure 2. Synthesis of allyl amines rac-6a–g from the corresponding allyl alcohols.
Table 2
Synthesis of allyl amines rac-6a–g from the corresponding allyl alcohols
Ar
4 Yield (%)
5 Yield (%)
rac-6 Yield (%)
a, 1-Naphthalenyl
95
89
93
94
95
96
98
96
95
95
96
95
95
97
88
79
76
77
87
91
73
b, 4-Methylphenyl
c, 3,5-Dimethylphenyl
d, 2-Methylphenyl
e, 2,4,6-Trimethylphenyl
f, 4-Methylnaphthalen-1-yl
g, Phenyl
The enzyme catalyzed resolution of racemic amines 6a–g were
screened with variety of lipases, but only lipase from
a
B
C. antarctica showed positive results. Next, three different CaLB
materials—lyophilized CaLB, Altus-11, and Novozym 435 were
tested separately. The best enantioselective results were with CaLB
immobilized on a polymer carrier (Novozym 435); as a result, the
remaining work was carried out with this lipase. The reaction
4.2. General procedure for the synthesis of acrylic esters 2a–f
To a solution of the corresponding aldehyde (1 equiv) and
DMAP (0.2 equiv) in DMF (2 mL per 1 mmol of aldehyde) ethyl

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A. Knezevic et al. / Tetrahedron: Asymmetry 22 (2011) 936–941
938
Table 3
CaLB catalyzed enantioselective acylation of racemic 1-aryl-allylamines 6a–g
O
NH2
HN
NH2
CaLB
+
acyl donor
Ar
rac-
Ar
Ar
solvent, 30 °C
6a-g
8a-g
Time (d)
6a-g
(S)-
Entry
Amine
Ar
1-Napthalenyl
4-Methylphenyl
3,5-Dimethylphenyl
2-Methylphenyl
2,4,6-Trimethylphenyl
2,4,6-Trimethylphenyl
4-Methylnaphthalen-1yl
Phenyl
Solvent
Acyl donor
Amine, ee (%)
Yielda (%)
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6e
6f
MTBE
Ethyl methoxyacetate
Ethyl methoxyacetate
iso-Propyl acetate
Ethyl methoxyacetate
iso-Propyl acetate
Ethyl methoxyacetate
Ethyl methoxyacetate
iso-Propyl acetate
5
3
7
8
4
4
2
2
>99.9
98.9
80.6
63.5
—
8.7
>99.9
>99.9
45
39
43
nib
0
Hexane
Hexane
MTBE
hexane
MTBE
nib
48
45
MTBE
Hexane
6g
a
Maximum yield is 50%.
Not isolated.
b
potassium malonate (1.5 equiv) was added. The resulting suspen-
sion was cooled to 0 °C and acetic acid (1.5 equiv) was added drop-
wise followed by piperidine (0.2 equiv). The reaction mixture was
stirred at 60 °C for 5–8 days until completion of the reaction. Water
was added and the mixture extracted with twice Et2O. The com-
bined organic extracts were washed with a saturated aqueous
solution of NH4Cl, followed by water, and a saturated aqueous
solution of NaHCO3, dried over Na2SO4, filtered, and concentrated
under reduced pressure.
NMR (75 MHz, CDCl3) d 167.03, 141.81, 137.23, 132.69, 131.41,
130.15, 126.43, 126.43, 126.02, 124.75, 123.92, 120.04, 60.51,
19.80, 14.37.
4.3. General procedure for the synthesis of alcohols 3a–f
To a solution of the corresponding acrylic ester (1 equiv) in dry
CH2Cl2 (5 mL per 1 mmol of ester), under argon, cooled to–30 °C,
diisobutylaluminium hydride (1.2 M solution in toluene, 2 equiv)
was added dropwise. The reaction mixture was stirred for 3 h at
ꢁ30 °C. Ethanol (2 mL per 1 mmol of ester) was added followed
by a saturated aqueous solution of potassium sodium tartrate (Ro-
chelle salt, 3 mL per 1 mmol of ester). The layers were separated
and the aqueous phase washed three times with DCM. The com-
bined organic layers were dried over Na2SO4, filtered, and concen-
trated under reduced pressure.
4.2.1. Ethyl-(E)-3-(1-naphthalenyl)-2-propenoate 2a
Yellow oil (6.9 g, 95%, E:Z > 99:1) starting from 1-naphthalde-
hyde (4.3 mL). NMR data were in accordance with the literature.12
4.2.2. Ethyl-(E)-3-(4-methylphenyl)-2-propenoate 2b
Yellow oil (6.1 g, 99%, E:Z > 99:1) starting from 4-methylbenzal-
dehyde (3.8 mL). NMR data were in accordance with the
literature.13
4.3.1. (E)-3-(1-Naphthalenyl)-prop-2-en-1-ol 3a
Yellow oil (5.3 g, 99%) starting from 2a (6.5 g). NMR data were
in accordance with the literature.15
4.2.3. Ethyl-(E)-3-(3,5-dimethylphenyl)-2-propenoate 2c
Yellow oil (3.7 g, 98%, E:Z > 99:1) starting from 3,5-dimethyl-
benzaldehyde (2.5 g).
m
max/cmꢁ1 1716, 1638, 1180, 1165, 1040,
982, 845, 677. 1H NMR (300 MHz, CDCl3)
d
7.63 (1H, d,
4.3.2. (E)-3-(4-Methylphenyl)-prop-2-en-1-ol 3b
White solid (4.0 g, 99%) starting from 2b (5.1 g). NMR data were
in accordance with the literature.16
J = 16.1 Hz, CH), 7.14 (2H, s, Ar), 7.02 (1H, s, Ar), 6.41 (1H, d,
J = 16.1 Hz, CH), 4.26 (2H, q, J = 7.3 Hz, CH2CH3), 2.33 (6H, s, ArCH3),
1.34 (3H, t, J = 7.3 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3) d 167.05,
144.85, 138.32, 134.39, 131.94, 125.89, 117.83, 60.32, 21.11, 14.28.
4.3.3. (E)-3-(3,5-Dimethylphenyl)-prop-2-en-1-ol 3c
Yellow oil (0.79 g, 98%) starting from 2c (1.0 g). m
max/cmꢁ1 3410,
1698, 1682, 1603, 968, 852, 690. 1H NMR (300 MHz, CDCl3) d 7.02
(2H, s, Ar), 6.90 (1H, s, Ar), 6.56 (1H, d, J = 16.1 Hz, CH), 6.34 (1H, dt,
J = 5.7, 16.1 Hz, CHCH2), 4.31 (2H, d, J = 5.7 Hz, CHCH2), 2.31 (6H, s,
ArCH3), 1.54 (1H, br s, OH); 13C NMR (75 MHz, CDCl3) d 138.04,
136.60, 131.42, 129.45, 128.13, 124.39, 63.82, 21.23.
4.2.4. Ethyl-(E)-3-(2-methylphenyl)-2-propenoate 2d
Yellow oil (3.2 g, 97%, E:Z > 99:1) starting from 2-methylbenzal-
dehyde (2.0 mL). NMR data were in accordance with the
literature.13
4.2.5. Ethyl-(E)-3-(2,4,6-trimethylphenyl)-2-propenoate 2e
White solid (0.53 g, 53%, E:Z > 99:1) starting from 2,4,6-trimeth-
ylbenzaldehyde (0.68 g); mp 38.8–39.6 °C. NMR data were in
accordance with the literature.14
4.3.4. (E)-3-(2-Methylphenyl)-prop-2-en-1-ol 3d
Yellow oil (0.75 g, 96%) starting from 2d (1.01 g).
m
max/cmꢁ1
3330, 1486, 1459, 1110, 1086, 967, 746. 1H NMR (300 MHz, CDCl3)
d 7.48–7.44 (1H, m, Ar), 7.20–7.15 (3H, m, Ar), 6.85 (1H, d,
J = 15.8 Hz, CH), 6.26 (1H, dt, J = 5.7, 15.8 Hz, CHCH2), 4.35 (2H, d,
J = 5.7 Hz, CHCH2), 2.37 (3H, s, ArCH3), 1.96 (1H, br s, OH); 13C
NMR (75 MHz, CDCl3) d 135.75, 135.42, 130.23, 129.83, 128.86,
127.50, 126.04, 125.69, 63.80, 19.69.
4.2.6. Ethyl-(E)-3-(4-methylnaphthalen-1-yl)-2-propenoate 2f
White solid (1.6 g, 95%, E:Z > 99:1) starting from 4-methyl-1-
naphthaldehyde (1.2 g); mp 76.9–77.9 °C; m
max/cmꢁ1 1703, 1632,
1306, 1183, 977, 830, 822, 759. 1H NMR (300 MHz, CDCl3) d 8.53
(1H, d, J = 15.9 Hz, CH), 8.25–8.21 (1H, m, Ar), 8.06–8.02 (1H, m,
Ar), 7.66 (1H, d, J = 7.4 Hz, Ar), 7.60–7.56 (2H, m, Ar), 7.33 (1H, d,
J = 7.4 Hz, Ar), 6.50 (1H, d, J = 15.9 Hz, CH), 4.33 (2H, q, J = 7.1 Hz,
CH2CH3), 2.72 (3H, s, ArCH3), 1.39 (3H, t, J = 7.1 Hz, CH2CH3); 13C
4.3.5. (E)-3-(2,4,6-Trimethylphenyl)-prop-2-en-1-ol 3e
White solid (0.50 g, 99%) starting from 2e (0.63 g). NMR data
were in accordance with the literature.14

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´
939
A. Knezevic et al. / Tetrahedron: Asymmetry 22 (2011) 936–941
4.3.6. (E)-3-(4-Methylnaphthalen-1-yl)-prop-2-en-1-ol 3f
White solid (1.72 g, 99%) starting from 2f (2.12 g); mp 100.2–
101.1 °C;
5.90 (1H, dt, J = 6.1, 16.3 Hz, CHCH2), 5.00 (2H, dd, J = 1.2, 6.1 Hz,
CHCH2), 2.27 (9H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 162.47,
136.56, 135.89, 132.99, 132.79, 128.59, 127.24, 69.70, 20.91, 20.76.
m
max/cmꢁ1 3340, 1412, 1015, 966, 840, 752. 1H NMR
(300 MHz, CDCl3) d 8.16–8.13 (1H, m, Ar), 8.04–8.01 (1H, m, Ar),
7.57–7.49 (3H, m, Ar), 7.37 (1H, d, J = 15.7 Hz, CH), 7.30 (1H, d,
J = 7.3 Hz, Ar), 6.36 (1H, dt, J = 5.7, 15.7 Hz, CHCH2), 4.43 (2H, d,
J = 5.7 Hz, CHCH2), 2.70 (3H, s, ArCH3), 1.61 (1H, br s, OH), 13C NMR
(75 MHz, CDCl3) d 134.36, 132.83, 132.63, 131.23, 131.08, 128.56,
126.50, 125.71, 125.65, 124.65, 124.31, 123.71, 64.04, 19.60.
4.4.6. (E)-3-(4-Methylnaphthalen-1-yl)-allyl-2,2,2-trichloro-
acetimidate 4f
Yellow oil (2.86 g, 96%) starting from 3f (1.72 g).
m
max/cmꢁ1
3375, 1695, 1385, 1112, 968, 835, 753. 1H NMR (300 MHz, CDCl3)
d 8.41 (1H, br s, NH), 8.14–8.12 (1H, m, Ar), 8.04–8.02 (1H, m,
Ar), 7.55–7.51 (4H, m, Ar, CH), 7.31 (1H, d, J = 7.44 Hz, Ar), 6.39
(1H, dt, J = 6.0, 15.6 Hz, CHCH2), 5.09 (2H, dd, J = 1.3, 6.0 Hz,
CHCH2), 2.70 (3H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 162.60,
134.84, 132.65, 132.35, 131.89, 131.24, 126.49, 125.89, 125.73,
124.79, 124.70, 124.24, 123.94, 69.88, 19.67.
4.4. General procedure for the synthesis of trichloroacetimid-
ates 4a–f
To a solution of the corresponding alcohol (1 equiv) and DBU
(0.2 equiv) in dry CH2Cl2 (6 mL per 1 mmol of alcohol) at 0 °C, tri-
chloroacetonitrile (1.1 equiv) was added dropwise. The reaction
mixture was stirred for 15 min. The solvent was evaporated to give
a brown residue which was filtered through a short column of neu-
tral aluminium oxide, activity I (eluent EtOAc/hexane = 10:90) to
afford the product.
4.4.7. (E)-3-Phenylallyl-2,2,2-trichloroacetimidate 4g
Yellow oil (1.06 g, 98%) starting from cinammyl alcohol
(0.52 g).7a
4.5. General procedure for the synthesis of amides 5a–g
To
a solution of the corresponding trichloroacetimidate
4.4.1. (E)-3-(1-Naphthalenyl)allyl-2,2,2-trichloroacetimidate 4a
(1 equiv) in xylene (6 mL per 1 mmol of trichloroacetimidate),
K2CO3 (2 mg/mL xylene) was added and the mixture was refluxed
at 140 °C for 24 h. The reaction mixture was cooled to room tem-
perature, concentrated under reduced pressure, and filtered
through a short column of silica gel (eluent toluene) to give a
product.
Yellow oil (9.0 g, 95%) starting from 3a (5.3 g).
m
max/cmꢁ1
3340, 1667, 1306, 1079, 970, 795. 1H NMR (300 MHz, CDCl3) d
8.42 (1H, br s, NH), 8.11 (1H, d, J = 8.0 Hz, Ar), 7.87–7.79 (2H, m,
Ar), 7.64 (1H, d, J = 7.1 Hz, Ar), 7.56–7.43 (4H, m, Ar, CH), 6.43
(1H, dt, J = 6.0, 15.6 Hz, CHCH2), 5.10 (2H, d, J = 5.9 Hz, CHCH2);
13C NMR (75 MHz, CDCl3) d 162.57, 133.96, 133.61, 131.51,
131.16, 128.58, 128.47, 126.25, 125.88, 125.58, 125.53, 124.15,
123.66, 69.71.
4.5.1. 2,2,2-Trichloro-N-[1-(1-naphthalenyl)allyl]acetamide 5a
White solid (7.75 g, 96%) starting from 4a (8.08 g); mp 109.3–
110.2 °C; C15H12Cl3NO requires C, 54.82; H, 3.68; N, 4.26, found:
C, 55.28; H, 3.52; N, 4.00. m
max/cmꢁ1 3284, 1685, 1526, 838, 823,
4.4.2. (E)-3-(4-Methylphenyl)allyl-2,2,2-trichloroacetimidate 4b
Yellow oil (3.97 g, 89%) starting from 3b (2.27 g).
m
max/cmꢁ1
804. 1H NMR (300 MHz, CDCl3) d 8.03 (1H, d, J = 8.2 Hz, Ar), 7.89
(2H, t, J = 9.2 Hz, Ar), 7.61–7.45 (4H, m, Ar), 6.89 (1H, br s, NH),
6.38–6.32 (1H, m, CHNH), 6.25 (1H, ddd, J = 4.4, 10.3, 17.3 Hz,
CHCH2), 5.46 (1H, d, J = 10.3, CH2CH), 5.41 (1H, d, J = 17.3, CH2CH);
13C NMR (75 MHz, CDCl3) d 161.02, 135.36, 134.27, 134.09, 131.13,
129.48, 129.00, 127.09, 126.26, 125.25, 125.20, 123.03, 116.74,
53.29.
3344, 1716, 1664, 1308, 1289, 1078, 968, 798. 1H NMR
(300 MHz, CDCl3) d 8.35 (1H, br s, NH), 7.32 (2H, d, J = 8.0 Hz, Ar),
7.14 (2H, d, J = 8.0 Hz, Ar), 6.73 (1H, d, J = 15.9 Hz, CH), 6.35 (1H,
dt, J = 6.3, 15.9 Hz, CHCH2), 4.96 (2H, dd, J = 1.2, 6.3 Hz, CHCH2),
2.35 (3H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 162.58, 138.07,
134.59, 133.36, 129.30, 126.62, 121.24, 69.93, 21.22.
4.5.2. 2,2,2-Trichloro-N-[1-(4-methylphenyl)allyl]acetamide 5b
White solid (3.56 g, 95%) starting from 4b (3.74 g); mp 78.5–
79.1 °C.
(300 MHz, CDCl3) d 7.20 (4H, s, Ar), 6.89 (1H, br s, NH), 6.04 (1H,
ddd, J = 5.3, 10.3, 17.2 Hz, CHCH2), 5.56–5.49 (1H, m, CHNH), 5.33
(1H, d, J = 10.3, CH2CH), 5.30 (1H, d, J = 17.2, CH2CH), 2.35 (3H, s,
ArCH3) ; 13C NMR (75 MHz, CDCl3) d 160.88, 138.18, 135.81,
135.74, 129.73, 127.07, 116.83, 56.85, 21.14.
4.4.3. (E)-3-(3,5-Dimethylphenyl)allyl-2,2,2-trichloroacetimid-
ate 4c
m
max/cmꢁ1 3297, 1695, 1523, 837, 819, 805. 1H NMR
Yellow oil (1.34 g, 93%) starting from 3c (0.77 g).
m
max/cmꢁ1
3376, 1696, 1608, 1381, 1110, 968, 837. 1H NMR (300 MHz, CDCl3)
d 8.35 (1H, br s, NH), 7.05 (2H, s, Ar), 6.92 (1H, s, Ar), 6.70 (1H, d,
J = 15.8 Hz, CH), 6.37 (1H, dt, J = 6.3, 15.8 Hz, CHCH2), 4.96 (2H,
dd, J = 1.2, 6.3 Hz, CHCH2), 2.32 (6H, s, ArCH3); 13C NMR (75 MHz,
CDCl3) d 162.60, 138.08, 136.09, 134.81, 129.88, 124.60, 121.93,
69.88, 21.21.
4.5.3. 2,2,2-Trichloro-N-[1-(3,5-dimethylphenyl)allyl]acetamide
5c
4.4.4. (E)-3-(2-Methylphenyl)allyl-2,2,2-trichloroacetimidate 4d
White solid (2.84 g, 95%) starting from 4c (2.98 g); mp 85.8–
Yellow oil (1.3 g, 94%) starting from 3d (0.70 g).
m
max/cmꢁ1
86.8 °C.
m
max/cmꢁ1 3294, 1698, 1529, 831, 822. 1H NMR
3343, 1668, 1308, 1285, 1078, 968, 798, 745. 1H NMR (300 MHz,
CDCl3) d 8.37 (1H, br s, NH), 7.49–7.45 (1H, m, Ar), 7.20–7.15
(3H, m, Ar), 6.99 (1H, d, J = 15.9 Hz, CH), 6.28 (1H, dt, J = 6.1,
15.9 Hz, CHCH2), 5.00 (2H, dd, J = 1.4, 6.1 Hz, CHCH2), 2.36 (3H, s,
ArCH3); 13C NMR (75 MHz, CDCl3) d 162.54, 135.73, 135.34,
132.22, 130.34, 127.99, 126.14, 125.84, 123.60, 69.78, 19.72.
(300 MHz, CDCl3) d 6.97 (1H, s, Ar), 6.93 (2H, s, Ar), 6.86 (1H, br
s, NH), 6.04 (1H, ddd, J = 5.3, 10.1, 17.4 Hz, CHCH2), 5.52–5.46
(1H, m, CHNH), 5.33 (1H, d, J = 10.1, CH2CH), 5.32 (1H, d, J = 17.4,
CH2CH), 2.33 (6H, s, ArCH3); 13C NMR (75 MHz, CDCl3) d 160.84,
138.73, 138.69, 135.82, 129.98, 124.89, 116.58, 57.07, 21.30.
4.5.4. 2,2,2-Trichloro-N-[1-(2-methylphenyl)allyl]acetamide 5d
White solid (1.69 g, 96%) starting from 4d (1.75 g); mp 69.2–
4.4.5. (E)-3-(2,4,6-Trimethylphenyl)allyl-2,2,2-trichloroacetim-
idate 4e
69.9 °C. m
max/cmꢁ1 3300, 1690, 1516, 836, 823, 758, 726. 1H NMR
Colorless oil (0.87 g, 95%) starting from 3e (0.5 g).
m
max/cmꢁ1
(300 MHz, CDCl3) d 7.24 (4H, s, Ar), 6.79 (1H, br s, NH), 6.06 (1H,
ddd, J = 4.6, 10.4, 17.2 Hz, CHCH2), 5.77–5.72 (1H, m, CHNH), 5.35
(1H, d, J = 10.4, CH2CH), 5.26 (1H, d, J = 17.2, CH2CH), 2.39 (3H, s,
3346, 1667, 1302, 1078, 979, 794. 1H NMR (300 MHz, CDCl3) d
8.36 (1H, br s, NH), 6.87 (2H, s, Ar), 6.75 (1H, d, J = 16.3 Hz, CH),

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´
A. Knezevic et al. / Tetrahedron: Asymmetry 22 (2011) 936–941
940
ArCH3); 13C NMR (75 MHz, CDCl3) d 136.68, 135.40, 131.09, 128.36,
126.57, 126.49, 116.59, 53.86, 19.09.
4.6.4. 1-(2-Methylphenyl)-prop-2-en-1-amine 6d
Yellow oil (0.30 g, 77%) starting from 5d (0.77 g). 1H NMR
(300 MHz, CDCl3) d 7.39 (1H, d, J = 7.2 Hz, Ar), 7.25–7.13 (3H, m,
Ar), 6.02 (1H, ddd, J = 5.7, 10.2, 17.2 Hz, CHCH2), 5.20 (1H, d,
J = 17.2, CH2CH), 5.12 (1H, d, J = 10.2, CH2CH), 4.76 (1H, d,
J = 5.7 Hz, CHNH2), 2.38 (3H, s, ArCH3), 1.90 (2H, br s, NH2); 13C
NMR (75 MHz, CDCl3) d 142.06, 141.34, 135.34, 130.48, 126.92,
126.33, 125.72, 113.85, 54.19, 19.17.
4.5.5. 2,2,2-Trichloro-N-[1-(2,4,6-trimethylphenyl)allyl]acetam-
ide 5e
Colorless oil (0.86 g, 95%) starting from 4e (0.91 g). m
max/cmꢁ1
3445, 1716, 1508, 837, 820, 737, 680. 1H NMR (300 MHz, CDCl3)
d 7.23 (1H, br s, NH), 6.87 (2H, s, Ar), 6.11–5.96 (2H, m, CHCH2,
CHNH), 5.27 (1H, d, J = 10.4, CH2CH), 5.12 (1H, d, J = 17.0, CH2CH),
2.40 (6H, s, ArCH3), 2.27 (3H, s, ArCH3); 13C NMR (75 MHz, CDCl3)
d 160.95, 137.61, 136.30, 135.74, 131.81, 130.25, 116.19, 53.02,
20.79, 20.60.
4.6.5. 1-(2,4,6-Trimethylphenyl)-prop-2-en-1-amine 6e
Yellow oil (0.38 g, 87%) obtained after silica gel column chro-
matography (CH2Cl2–MeOH, 9:1, Rf = 0.44) starting from 5e
(0.80 g).
m
max/cmꢁ1 3400, 1669, 1662, 1611, 1383, 1266, 917,
852, 737. 1H NMR (300 MHz, CDCl3) d 6.83 (2H, s, Ar), 6.14
(1H, ddd, J = 4.1, 10.3, 17.0 Hz, CHCH2), 5.17 (1H, d, J = 17.0,
CH2CH), 5.12 (1H, d, J = 10.3, CH2CH), 5.02–4.97 (1H, m, CHNH2),
2.37 (6H, s, ArCH3), 2.25 (3H, s, ArCH3), 1.60 (2H, br s, NH2); 13C
NMR (75 MHz, CDCl3) d 141.26, 137.22, 136.22, 130.11, 113.03,
53.32, 20.79, 20.68.
4.5.6. 2,2,2-Trichloro-N-[1-(4-methylnaphthalen-1-yl)allyl]acet-
amide 5f
White solid (2.92 g, 95%) starting from 4f (3.08 g). mp 116.4–
117.2 °C.
m
max/cmꢁ1 3316, 1687, 1507, 826, 760. 1H NMR
(300 MHz, CDCl3) d 8.41 (1H, br s, NH), 8.14–8.12 (1H, m, Ar),
8.04–8.02 (1H, m, Ar), 7.55–7.51 (4H, m, Ar, CH), 7.31 (1H, d,
J = 7.44 Hz, Ar), 6.39 (1H, dt, J = 6.0, 15.6 Hz, CHCH2), 5.09 (2H,
dd, J = 1.3, 6.0 Hz, CHCH2), 2.70 (3H, s, ArCH3); 13C NMR (75 MHz,
CDCl3) d 160.98, 135.85, 135.48, 133.23, 132.43, 131.16, 126.72,
126.10, 125.96, 125.08, 123.54, 116.53, 53.26, 19.66.
4.6.6. 1-(4-Methylnaphthalen-1-yl)-prop-2-en-1-amine 6f
Yellow oil (0.48 g, 91%) obtained after silica gel column chro-
matography (CH2Cl2–MeOH, 9:1, Rf = 0.54) starting from 5e
(0.91 g).
m
max/cmꢁ1 3375, 1637, 1598, 1391, 1264, 920, 836,
4.5.7. 2,2,2-Trichloro-N-(1-phenylallyl)acetamide 5g
White solid (1.03 g, 97%) starting from 4g (1.06 g).7a
755. 1H NMR (300 MHz, CDCl3) d 8.26–8.20 (1H, m, Ar), 8.08–
8.02 (1H, m, Ar), 7.58–7.52 (2H, m, Ar), 7.47 (1H, d, J = 7.2 Hz,
Ar), 7.32 (1H, d, J = 7.2 Hz, Ar), 6.22 (1H, ddd, J = 5.7, 10.3,
17.1 Hz, CHCH2), 5.39–5.29 (2H, m, CH2CH, CHNH2), 5.22 (1H,
d, J = 10.3, CH2CH), 2.69 (3H, s, ArCH3), 1.78 (2H, br s, NH2);
13C NMR (75 MHz, CDCl3) d 141.70, 138.08, 133.35, 133.07,
131.05, 126.35, 125.72, 125.43, 124.97, 123.92, 123.28, 114.28,
53.85, 19.59.
4.6. General procedure for the synthesis of racemic amines 6a–g
To a solution of the corresponding amide (1 equiv) in absolute
ethanol (5 mL per 1 mmol of amide), 5 M NaOH solution in water
(30 equiv) was added and the mixture was stirred at room temper-
ature for 24 h. The reaction mixture was concentrated to an aque-
ous residue which was acidified to pH 1 by the addition of 6 M HCl
and washed three times with CH2Cl2. Next, Na2CO3 was added to
the aqueous layer until pH 8. The mixture was then extracted three
times with diethyl ether. The combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced pressure.
4.6.7. 1-Phenyl-prop-2-en-1-amine 6g
Yellow oil (0.35 g, 73%) starting from 5g (1.01 g). NMR data
were in accordance with the literature.11
4.7. General procedure for the enzymatic resolution of racemic
amines
4.6.1. 1-(1-Naphthalenyl)-prop-2-en-1-amine 6a
Yellow oil (3.82 g, 88%) starting from 5a (7.75 g).
m
max/cmꢁ1
3300, 1669, 1638, 1594, 1393, 802, 779. 1H NMR (300 MHz, CDCl3)
d 8.19 (1H, d, J = 8.2 Hz, Ar), 7.91–7.85 (1H, m, Ar), 7.81–7.75 (1H,
m, Ar), 7.62–7.43 (4H, m, Ar), 6.23 (1H, ddd, J = 5.2, 10.4, 17.5 Hz,
CHCH2), 5.40–5.31 (2H, m, CH2CH, CHNH2), 5.23 (1H, d,
J = 10.4 Hz, CH2CH), 2.29 (2H, br s, NH2); 13C NMR (75 MHz, CDCl3)
d 141.24, 139.60, 133.95, 130.92, 128.88, 127.84, 126.05, 125.53,
123.52, 123.32, 114.55, 53.84.
The racemic amine (1 equiv) was dissolved in a mixture of
iso-propyl acetate (14 mL per 1 mmol of amine) and hexane
(2 mL per 1 mmol of hexane). Immobilized lipase B from C. ant-
arctica, Novozym 435 (0.3 g per 1 mmol of amine) was added.
The reaction mixture was stirred at 30 °C. The progress of the
reaction was monitored using HPLC, on Chiralcel OD-H column
(hexane–2-propanol–diethylamine, 90:10:0.1). After completion
of the reaction, the reaction mixture was filtered and the filtrate
concentrated. Next, 1 M HCl was added (3.5 mL per 1 mmol of
starting amine). The mixture was washed three times with
dichloromethane. Next, Na2CO3 was added to the aqueous layer
until pH 8 was obtained. The mixture was extracted three times
with diethyl ether. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure.
4.6.2. 1-(4-Methylphenyl)-prop-2-en-1-amine 6b
Yellow oil (1.34 g, 79%) starting from 5b (3.36 g).
m
max/cmꢁ1
3375, 3300, 1638, 1511, 917, 818, 761. 1H NMR (300 MHz, CDCl3)
d 7.24 (2H, d, J = 7.9 Hz , Ar), 7.15 (2H, d, J = 7.9 Hz, Ar), 6.02 (1H,
ddd, J = 6.1, 10.2, 17.1 Hz, CHCH2), 5.23 (1H, d, J = 17.1, CH2CH),
5.10 (1H, d, J = 10.2, CH2CH), 4.50 (1H, d, J = 6.1 Hz, CHNH2), 2.34
(3H, s, ArCH3), 1.66 (2H, br s, NH2); 13C NMR (75 MHz, CDCl3) d
142.37, 141,46, 136.70, 129.19, 126.49, 113.47, 58.06, 21.02.
4.7.1. (S)-1-(1-Naphthalenyl)-prop-2-en-1-amine (S)-6a
Yield 45%, ee >99.9%, Chiralcel OD-H column, hexane-2-propa-
nol-diethylamine, 90:10:0.1, 1 mL/min, 300 nm, tR(S) = 9.0 min,
4.6.3. 1-(3,5-Dimethylphenyl)-prop-2-en-1-amine 6c
m
max/cmꢁ1
tR(R) = 10.1 min; ½a D25
ꢂ
¼ ꢁ46:0 (c 0.9, CHCl3).
Yellow oil (0.80 g, 76%) starting from 5c (2.00 g).
3375, 1638, 1607, 1466, 995, 918, 848, 734. 1H NMR (300 MHz,
CDCl3) d 6.96 (2H, s, Ar), 6.90 (1H, s, Ar), 6.02 (1H, ddd, J = 6.1,
10.2, 17.1 Hz, CHCH2), 5.25 (1H, d, J = 17.1, CH2CH), 5.11 (1H, d,
J = 10.2, CH2CH), 4.46 (1H, d, J = 6.1 Hz, CHNH2), 2.32 (6H, s, ArCH3),
1.63 (2H, br s, NH2); 13C NMR (75 MHz, CDCl3) d 144.38, 142.35,
138.06, 128.71, 124.37, 113.41, 58.31, 21.25.
4.7.2. (S)-1-(4-Methylphenyl)-prop-2-en-1-amine (S)-6b
Yield 39%, ee 98.9%, Chiralcel OD-H column, hexane-2-propa-
nol-diethylamine, 90:10:0.1, 1 mL/min, 268 nm, tR(R) = 5.7 min,
tR(S) = 6.4 min; ½a D25
¼ ꢁ9:7 (c 1.1, CH2Cl2).
ꢂ

ˇ
´
941
A. Knezevic et al. / Tetrahedron: Asymmetry 22 (2011) 936–941
2. For some examples, see: (a) Ichikavata, Y.; Ito, T.; Nishiyama, T.; Isobe, M.
Synlett 2003, 1034–1036; (b) Chen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem.
Soc. 2002, 124, 12225–12231.
4.7.3. (S)-1-(3,5-Dimethylphenyl)-prop-2-en-1-amine (S)-6c
Yield 39%, ee 80.6%, Chiralcel OD-H column, hexane-2-propa-
nol-diethylamine, 90:10:0.1, 1 mL/min, 240 nm, tR(R) = 5.0 min,
tR(S) = 5.3 min.
3. Gotor-Fernández, V.; Busto, E.; Gotor, V. Adv. Synth. Catal. 2006, 348, 797–812.
ˇ
´
´
´
4. (a) Gazic´ Smilovic´, I.; Molcanov, K.; Vinkovic, V.; Kojic-Prodic, B.; Lesac, A. J.
Mol. Struct. 2010, 980, 51–58; (b) Moslavac Forjan, D.; Vinkovic´, M.; Kontrec, D.;
´
´
Lesac, A.; Vinkovic, V. Struct. Chem. 2007, 18, 585–591; (c) Landek, G.; Vinkovic,
M.; Kontrec, D.; Vinkovic´, V. Chromatographia 2006, 64, 469–473; (d) Moslavac
4.7.4. (S)-1-(4-Methylnaphthalen-1-yl)-prop-2-en-1-amine (S)-
6f
´
´
´
Forjan, D.; Gazic, I.; Vinkovic, V. Chirality 2007, 19, 446–452; (e) Gazic, I.;
Kontrec, D.; Lesac, A.; Vinkovic´, V. Tetrahedron: Asymmetry 2005, 16, 1175–
1182.
Yield 48%, ee >99.9%, Chiralcel OD-H column, hexane-2-propa-
nol-diethylamine, 95:5:0.1, 1 mL/min, 300 nm, tR(S) = 11.7 min,
5. (a) Pirkle, W. H.; Welch, C. J.; Lamm, B. R. U.S. Patent 5,387,338 A, 1995.; (b)
Hyun, M. H.; Kim, K. J.; Jyung, K. K. Bull. Korean Chem. Soc. 1997, 18, 1085–1089;
tR(R) = 13.3 min; ½a D25
¼ ꢁ40:2 (c 3.2, CH2Cl2).
ꢂ
´
(c) Moslavac Forjan, D.; Kontrec, D.; Vinkovic, V. Chirality 2006, 18, 857–869.
6. For overview of allylic amination, see: (a) Johannsen, M.; Jørgensen, K. A. Chem.
Rev. 1998, 98, 1689–1708; (b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103,
2921–2944; (c) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258–297.
7. (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597; (b) Overman, L. E. J. Am. Chem.
Soc. 1976, 98, 2901–2910; (c) Overman, L. E. Acc. Chem. Res. 1980, 13, 218–224;
(d) Overman, L. E. In Organic Reactions; John Wiley & Sons: New York, 2005;
Vol. 66,
8. List, B.; Doehring, A.; Hechavarria Fonseca, M. T.; Job, A.; Rios Torres, R.
Tetrahedron 2006, 62, 476–482.
9. Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc. 2003, 125, 12412–12413.
10. (a) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org.
Chem. 1991, 56, 2656–2665; (b) Rotticci, D.; Hæffner, F.; Orrenius, C.; Norin, T.;
Hult, K. J. Mol. Catal. B: Enzym. 1998, 5, 267–272.
4.7.5. (S)-1-Phenyl-prop-2-en-1-amine (S)-6g
Yield 45%, ee >99.9%, Chiralcel OD-H column, hexane-2-propa-
nol-diethylamine, 95:5:0.2, 1 mL/min, 254 nm, tR(R) = 7.4 min, tR(S)
= 9.1 min; ½a 2D5
¼ ꢁ10:2 (c 3.3, CHCl3); lit. value ascribed for (S)-
ꢂ
6g with ee >99.6% is ½a D25
ꢂ
¼ ꢁ10:45 (c 4, CHCl3).11
Acknowledgments
This work was supported by Ministry of Science, Education, and
Sports of Croatia (Grant No. 098-0982904-2910).
11. Pallavicini, M.; Valoti, E.; Villa, L.; Piccolo, O. Tetrahedron: Asymmetry 2000, 11,
4017–4025.
12. Dickinson, J. M.; Murphy, J. A.; Patterson, C. W.; Wooster, N. F. J. Chem. Soc.,
Perkin Trans. 1 1990, 1179–1184.
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